Combination antiretroviral therapy for the treatment of HIV infection has resulted in the metamorphosis of HIV-1 infection from a near uniformly fatal infection to one that is chronic and manageable with a now widely commercially available variety of simple and well tolerated treatment regimens. As such, the research focus of the Markowitz Lab has shifted from treatment to prevention.

It was a natural extension for our group to bring our expertise in the area of antiretroviral therapy into the prevention arena given documented success of daily oral fixed dose combination tenofovir disoproxil fumarate/emtricitabine (Truvada) as pre-exposure prophylaxis in individuals at high risk of contracting HIV infection. However, the results of clinical trials and demonstration projects suggest that though highly effective when individuals are adherent to treatment, not all high-risk individuals can adhere to the requisite treatment regimen. Our emphasis has been to search antiviral agents with promise as PrEP agents that may be good alternatives to daily oral therapy. Along these lines we have been working on two- the long acting long acting injectable cabotegravir (CAB LA), a novel inhibitor of HIV-1 integrase and MK-8591 aka EFdA (4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine), a nucleoside reverse transcriptase translocation inhibitor.

CAB LA has entered the clinic and is in Phase 3 clinical trials being conducted by the HIV Prevention Trials Network. To complement the global development plan, Dr. Markowitz and colleagues have worked in close collaboration with GlaxoSmithKline to develop a China CAB LA Program which will test the efficacy of CAB LA in high risk men who have sex with men and transgender women.

Studies with EFdA, aka MK-8591, remain preclinical. To date we have established 100% protection of a 3.9mg/kg weekly oral dose of MK-8591 against low dose rectal challenge with a recombinant simian/human immunodeficiency virus. Additional studies are being conducted at lower doses of MK-8591 to identify minimal drug concentrations at which protection may be maintained. It is anticipated that this compound may be amenable to administration via an implantable device capable of delivering therapeutic levels of drug over a prolonged period.

Future projects being considered include optimization of long acting combination antiviral therapy in the non-human primate model to facilitate HIV cure research as well as applying novel agents to understand remaining questions surrounding drug penetration in tissue and the possibility of ongoing viral replication despite apparently suppressive cART- an ongoing and important controversy in the field.

Now that HIV infection has become a treatable and chronic infection the Markowitz Lab has been spurred on to use their expertise in antiviral therapy to provide pre-clinical and clinical support for the development of novel antiviral agents to prevent the transmission of HIV infection otherwise known as pre-exposure prophylaxis or PrEP. Randomized clinical trials found that PrEP use was highly effective only when study participants were taking their medications regularly. As not all individuals are willing to take pills daily or even before and after exposure, alternatives that provide long acting protection may be more desirable. This use of PrEP is growing exponentially and similar to birth control, one size does not fit all. Therefore, the more delivery choices from which high risk individuals may choose, the more likely PrEP will be widely adopted. Combined with treatment as prevention, the widespread use of PrEP can have a profound effect on the future of the HIV epidemic here in the United States and elsewhere.

Meyers K, Rodriguez K, Moeller RW, Gratch I, Markowitz, M, Halkitis PN3. High Interest in a Long-Acting Injectable Formulation of Pre-Exposure Prophylaxis for HIV in Young Men Who Have Sex with Men in NYC: A P18 Cohort Substudy. PLoS One. 2014 Dec 11;9(12):e114700.

II International Consensus Symposium on Combined Antiviral Therapy and Implications for Future Therapies. "Ritonavir in Combination with Antiretroviral Agents". Barcelona, Spain. August 1996. Sponsored by the International Society for Antiviral Research.